EP2914575B1 - Plasminogen activator-1 inhibitors and methods of use thereof - Google Patents

Plasminogen activator-1 inhibitors and methods of use thereof Download PDF

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EP2914575B1
EP2914575B1 EP13850232.3A EP13850232A EP2914575B1 EP 2914575 B1 EP2914575 B1 EP 2914575B1 EP 13850232 A EP13850232 A EP 13850232A EP 2914575 B1 EP2914575 B1 EP 2914575B1
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pai
disease
compounds
compound
group
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English (en)
French (fr)
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EP2914575A4 (en
EP2914575A1 (en
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Daniel A. Lawrence
Cory Emal
Ashley REINKE
Shih-Hon Li
Mark Warnock
Gregory ABERNATHY
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Eastern Michigan University
University of Michigan
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University of Michigan
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Definitions

  • the invention generally relates to compositions and uses thereof for modulating plasminogen activator inhibitor-1 (PAI-1) activity. More particularly, the invention is directed to methods of identifying inhibitors of PAI-1 and the uses of such inhibitors in regulating PAI-1 activity. The invention also relates to uses of these inhibitors for the treatment of many diseases or disorders associated with PAI-1 activity. Such diseases or disorders include, but are not limited to, dysregulation of lipid metabolism, obesity, diabetes, polycystic ovary syndrome, bone loss induced by estrogen deficiency, fibrosis and fibrotic disease, inflammation, cell migration and migration-driven proliferation of cells, angiogenesis, and thrombosis. Such inhibitors are also contemplated to be useful for modulation of endogenous fibrinolysis, and in conjunction with pharmacologic thrombolysis.
  • Plasminogen activator inhibitor-1 is a 50 kDa single-chain glycoprotein that is the principal inhibitor of both urokinase type plasminogen activator (uPA) and tissue type PA (tPA). PAI-1 inhibits tPA and uPA with second-order rate constants ⁇ 10 7 M -1 s -1 , a value that is 10-1000 times faster than the rates of PA inhibition by other PAIs. Moreover, approximately 70% of the total tPA in carefully collected normal human plasma is detected in complex with PAI-1, suggesting that inhibition of tPA by PAI-1 is a normal, ongoing process. PAI-1 can also directly inhibit plasmin.
  • PAI-1 is the chief regulator of plasmin generation in vivo , and as such it appears to play an important role in both fibrotic and thrombotic disease.
  • PAI-1 has three potential N-linked glycosylation sites and contains between 15 and 20% carbohydrate.
  • PAI-1 belongs to the S erine P rotease In hibitor super family (SERPIN), which is a gene family that includes many of the protease inhibitors found in blood, as well as other proteins with unrelated or unknown functions. Serpins are consumed in the process of protease inactivation and thus act as "suicide inhibitors.”
  • the association between a serpin and its target protease occurs at an amino acid residue, referred to as the "bait” residue, located on a surface loop of the serpin called the reactive center loop (RCL).
  • the "bait” residue is also called the P1 residue, and is thought to mimic the normal substrate of the enzyme.
  • Native PAI-1 exists in at least two distinct conformations, an active form that is produced by cells and secreted, and an inactive or latent form that accumulates in cell culture medium over time. In blood and tissues, most of the PAI-1 is in the active form; however, in platelets both active and latent forms of PAI-1 are found.
  • active PAI-1 the RCL is exposed on the surface of the molecule, but upon reaction with a protease, the cleaved RCL integrates into the center of ⁇ sheet A.
  • the latent form the RCL is intact, but instead of being exposed, the entire amino terminal side of the RCL is inserted as the central strand into the ⁇ sheet A. This accounts for the increased stability of latent PAI-1 as well as its lack of inhibitory activity.
  • Active PAI-1 spontaneously converts to the latent form with a half-life of one to two hours at 37°C, and latent PAI-1 can be converted back into the active form by treatment with denaturants. Negatively charged phospholipids can also convert latent PAI-1 to the active form, suggesting that cell surfaces may modulate PAI-1 activity.
  • the observation that latent PAI-1 infused into rabbits is apparently converted to the active form is consistent with this hypothesis.
  • the spontaneous reversible interconversion between the active and latent structures is unique for PAI-1 and distinguishes it from other serpins; however, the biological significance of the latent conformation remains unknown.
  • PAI-1 non-inhibitory forms of PAI-1 have also been identified.
  • the first form results from oxidation of one or more critical methionine residues within active PAI-1.
  • This form differs from latent PAI-1 in that it can be partially reactivated by an enzyme that specifically reduces oxidized methionine residues.
  • Oxidative inactivation of PAI-1 may be an additional mechanism for the regulation of PAI-1, and oxygen radicals produced locally by neutrophils or other cells may inactivate PAI-1 and thus facilitate the generation of plasmin at sites of infection or in areas of tissue remodeling.
  • PAI-1 also exists in two different cleaved forms. As noted above, PAI-1 in complex with a protease is cleaved in its RCL.
  • Uncomplexed PAI-1 can also be found with its RCL cleaved, which can arise from dissociation of PAI-1-PA complexes or from cleavage of the RCL by a non-target protease at a site other than the P1. None of these forms of PAI-1 are able to inhibit protease activity; however, they may interact with other ligands.
  • PAI-1 binds with high affinity to heparin, the cell adhesion protein vitronectin, and members the endocytic low-density lipoprotein receptor (LDL-R) family, such as the lipoprotein receptor-related protein (LRP), and the very low density lipoprotein receptor (VLDL-R).
  • LDL-R low-density lipoprotein receptor
  • LRP lipoprotein receptor-related protein
  • VLDL-R very low density lipoprotein receptor
  • the PAI-1 binding site for vitronectin has been localized to a region on the edge of ⁇ -sheet A in the PAI-1 structure.
  • the binding site for LDL-R family members is less well characterized, but has been identified, in a region of PAI-1 associated with alpha helix D that is adjacent to the vitronectin binding domain.
  • the heparin binding domain on PAI-1 has also been mapped. This site also localizes to alpha helix D in a region homologous to the heparin binding domain of antithrombin III, and may overlap with the binding site for LDL-R family members.
  • Vitronectin circulates in plasma and is present in the extracellular matrix primarily at sites of injury or remodeling. PAI-1 and vitronectin appear to have a significant functional interdependence. Vitronectin stabilizes PAI-1 in its active conformation, thereby increasing its biological half-life.
  • Vitronectin also enhances PAI-1 inhibitory efficiency for thrombin approximately 300-fold.
  • PAI-1 binding to vitronectin alters its conformation from the native plasma form, which does not support cell adhesion, to an "activated" form that is competent to bind integrins.
  • integrin binding is blocked by the presence of PAI-1.
  • the association of PAI-1 with vitronectin is conformationally controlled and upon inhibition of a protease, the conformational change in PAI-1 associated with RCL insertion results in a loss of high affinity for vitronectin and a gain in affinity for LDL-R family members.
  • High PAI-1 levels are associated with various diseases and disorders.
  • high PAI-1 levels are associated with acute diseases, such as sepsis and myocardial infarction, and chronic disorders, such as cancer, atherosclerosis, and type 2 diabetes.
  • high PAI-1 levels are associated with cardiovascular disease, wherein PAI-1 expression is significantly increased in severely atherosclerotic vessels, and PAI-1 protein levels rise consistently during disease progression from normal vessels to fatty streaks to atherosclerotic plaques. Increased PAI-1 levels are also linked to obesity, and insulin resistance.
  • PAI-1 PAI-1-binding protein-1
  • thrombotic events thrombotic events
  • antibody neutralization of PAI-1 activity resulted in promotion of endogenous thrombolysis and reperfusion.
  • Elevated levels of PAI-1 have also been implicated in polycystic ovary syndrome and bone loss induced by estrogen deficiency.
  • PAI-1 is synthesized in both murine and human adipocytes. There is also a strong correlation between the amount of visceral fat and plasma levels of PAI-1 in humans and mice. This dramatic up-regulation of PAI-1 in obesity has lead to the suggestion that adipose tissue itself may directly contribute to elevated systemic PAI-1, which in-turn increases the probability of vascular disease through increased thrombosis, and accelerated atherosclerosis. Notably, very recent data suggests that PAI-1 may also play a direct role in obesity.
  • PAI-1 plays a previously unrecognized direct role in obesity and insulin resistance that involves interactions beyond its identified activities of modulating fibrinolysis and tissue remodeling.
  • PAI-1 positively regulates adipose tissue development
  • association of increased PAI-1 expression with developing obesity may constitute a positive feedback loop promoting adipose tissue expansion and dysregulation of normal cholesterol homeostasis.
  • the invention provides methods of identifying and using inhibitors of PAI-1.
  • the present invention relates to the following embediments defined under items 1-8:
  • plasminogen activator inhibitor-1 PAI-1
  • uses include, but are not limited to, the treatment of many diseases or disorders associated with elevated PAI-1 levels or activity as discussed herein below.
  • compositions comprising isolated PAI-1 inhibitors and a pharmaceutically acceptable carrier, wherein the PAI-1 inhibitors are present in an amount effective to inhibit PAI-1.
  • PAI-1 inhibitors include, but are not limited to, any of the compounds of Formulas I to XXIX or any of the compounds depicted in Tables 1, 3, 5, 7, 9, 11, 12, and 14, including C256, C259, C265, C267, C276, C277, C288, C309, C311, C280, C300, C313, C314, C320, C323, C326, C328, C334, C342, C240, C241, C246, C248, C251, C255, C260, C261, C262, C263, C264, C266, C268, C278, C281, C282, C287, C289, C295, C296, C297, C301, C304, C305, C307, C310, C322, C336, C339, C340, C341, C362, C279, C285, C286, C299, C306, C330, C344, C345, C346, C347, C348, C356, C357, C
  • the use thereof for treating or preventing a disease or disorder associated with elevated levels of PAI-1 or elevated PAI-1 activity.
  • the uses comprise administering a PAI-1 inhibitor to the subject in an amount effective to treat the disease or disorder.
  • the disease or disorder includes, but is not limited to, cancer, septicemia, a disorder associated with a dysregulation of lipid metabolism, a proliferative disease or disorder, psoriasis, fibrosis and fibrotic disease, coagulation homeostasis, cerebrovascular disease, vascular disease, microvascular disease, hypertension, dementia, atherosclerosis, osteoporosis, osteopenia, arthritis, asthma, heart failure, arrhythmia, angina, hormone insufficiency, Alzheimer's disease, inflammation, sepsis, fibrinolytic disorder, stroke, dementia, coronary heart disease, myocardial infarction, stable and unstable angina, peripheral arterial disease, acute vascular syndrome, thrombosis, prothrombosis, pulmonary embolism,
  • the disease or disorder involving thrombosis or prothrombosis includes, but is not limited to, formation of atherosclerotic plaques, venous and/or arterial thrombosis, deep vein thrombosis, arterial thrombosis, myocardial ischemia, atrial fibrillation, deep vein thrombosis, a coagulation syndrome, pulmonary thrombosis, cerebral thrombosis, a thromboembolic complication of surgery, and peripheral arterial occlusion.
  • the disease or disorder involving microvascular disease includes, but is not limited to, nephropathy, neuropathy, retinopathy and nephrotic syndrome.
  • the disease or disorder involving fibrosis or an extracellular matrix accumulation includes, but is not limited to, renal fibrosis, chronic obstructive pulmonary disease, polycystic ovary syndrome, restenosis, renovascular disease, diabetic nephropathy, or organ transplant rejection.
  • the disease or disorder involving dysregulation of lipid metabolism includes, but is not limited to, high cholesterol, elevated triglycerides, elevated levels of VLDL or LDL, and low levels of HDL.
  • the PAI-1 inhibitor compounds disclosed herein are used in methods of modulating cholesterol and/or lipid uptake and/or lipid clearance.
  • the PAI-1 inhibitor compounds decrease PAI-1 binding to ApoE, ApoA, VLDL, VLDL-R, ApoA-R, or LDL.
  • the PAI-1 inhibitor compounds bind to PAI-1 in the presence of vitronectin and/or uPA.
  • the PAI-1 inhibitor is administered to a subject in an amount effective to inhibit VLDL or ApoE or ApoA binding to VLDL-R. In one aspect, the PAI-1 inhibitor is administered to a subject in an amount effective to affect HDL or ApoE or ApoA binding to an ApoA receptor. In particular aspects, the PAI-1 inhibitor is used to increase HDL and/or decrease VLDL in a subject.
  • the PAI-1 inhibitor compounds of the invention are useful for modulation of endogenous fibrinolysis and for use in pharmacologic thrombolysis.
  • the subject is human.
  • the compounds of the invention are inhibitors of the serine protease inhibitor PAI-1, and are therefore useful in the treatment or prophylaxis of those processes which involve the production and/or action of PAI-1.
  • the invention describes materials and methods for the inhibition of plasminogen activator inhibitor-1 (PAI-1).
  • PAI-1 plasminogen activator inhibitor-1
  • the invention describes PAI-1 inhibitor compounds.
  • haloalkyl refers to a hydrocarbon group substituted with one or more halogens selected from F, Cl, Br, and I.
  • cycloalkyl refers to a cyclic hydrocarbon group, e.g., cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • heterocycloalkyl or “heterocyclic ring” refers to a cyclic hydrocarbon group having one or more heteroatoms, for example, one to three heteroatoms, independently selected from the group consisting of oxygen, nitrogen, and sulfur.
  • Exemplary aryl groups include, but are not limited to, phenyl, tolyl, naphthyl, tetrahydronaphthyl, chlorophenyl, methylphenyl, methoxyphenyl, trifluoromethylphenyl, nitrophenyl, 2,4-methoxychlorophenyl, and the like.
  • heteroaryl refers to a monocyclic or polycyclic ring system containing one or more aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring.
  • heteroaryl groups include, but are not limited to, thienyl, furyl, pyridyl, oxazolyl, quinolyl, thiophenyl, isoquinolyl, indolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl, imidazolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl.
  • amino acid refers to naturally occurring and non-natural amino acids, as well as amino acid analogs.
  • Naturally encoded amino acids include the 20 common amino acids (alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine), pyrrolysine, and selenocysteine.
  • Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, for example, 3-nitrotyrosine, homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (such as 3-nitrotyrosine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Amino acid analogs also include amino acid esters (e.g., amino acid alkyl esters, such as amino acid methyl esters) and acylated amino acids (e.g., acetylated amino acids).
  • amino acid esters e.g., amino acid alkyl esters, such as amino acid methyl esters
  • acylated amino acids e.g., acetylated amino acids
  • a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, prodrugs, salts of such prodrugs, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • a “pharmaceutically acceptable salt” means any salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 .
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, glutamate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
  • Salts of compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base.
  • suitable base include, but are not limited to, alkali metal, alkaline earth metal, aluminum salts, ammonium, N + (C 1-4 alkyl) 4 salts, and salts of organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, dicyclohexylamine, N,N'-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and basic amino acids such as lysine and arginine.
  • This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • prodrug refers to compounds that are rapidly converted to an active form (i.e., drug) within the body or cells thereof by the action of endogenous enzymes or other chemicals and/or conditions. Prodrug design is discussed generally in Hardma et al. (Eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed., pp. 11-16 (1996 ).
  • Prodrugs of the compounds disclosed herein include, but are not limited to, esters formed from available hydroxyl or carboxyl groups (also referred to as ester prodrugs or prodrug esters), amides formed from available amino, amido, or carboxyl groups, thioesters formed from available thiol or carboxyl groups, carbonates formed from available hydroxyl or carboxyl groups, carbamates formed from available hydroxyl, amino, or amido groups, carbamides formed from available amido or amino groups, sulfonate esters and sulfate esters formed from available hydroxyl groups, sulfonamides formed from available amino groups, and phosphonamides formed from available amino groups.
  • Suitable ester prodrugs include, but are not limited to, aliphatic esters, aryl esters, benzyl esters, and derivatives thereof.
  • R 1 is selected from C 1 to C 12 alkyl, -L 1 -C 3 -C 6 cycloalkyl, - L 2 -C 2 -C 6 heterocycloalkyl, benzyl, -L 3 -aryl, and -L 4 -heteroaryl, and is optionally substituted with one, two, three, or more substituent groups that are the same or different.
  • Suitable substituent groups include, but are not limited to, F, Cl, Br, I, CF 3 , CH 3 , OCF 3 , OCH 3 , and -CN.
  • Additional R 1 groups include, but are not limited to, optionally substituted phenyl, halophenyl (e.g., fluorophenyl, chlorophenyl, bromophenyl, iodophenyl), dihalophenyl (e.g., difluorophenyl, dichlorophenyl, dibromophenyl, diiodophenyl), trihalophenyl (e.g., trifluorophenyl, trichlorophenyl, tribromophenyl, triiodophenyl), (trifluoromethyl)phenyl, fluoro(trifluoromethyl)phenyl, chloro(trifluoromethyl)phenyl, bromo(trifluoromethyl)phenyl, iodo(trifluoromethyl)phenyl, tolyl, xylyl, fluorotolyl, chlorotolyl, bromotolyl, iodoto
  • R 4 , R 14 , R 15 , and R 16 are independently selected from -L 12 -C 3 -C 6 cycloalkyl, - L 13 -C 2 -C 6 heterocycloalkyl, benzyl, -L 14 -aryl, and -L 15 -heteroaryl, and are optionally substituted with one, two, three, or more substituent groups that are the same or different.
  • Suitable substituent groups include, but are not limited to, F, Cl, Br, I, CF 3 , CH 3 , OCF 3 , OCH 3 , and -CN.
  • R 4 , R 14 , R 15 , and R 16 groups include, but are not limited to, optionally substituted phenyl, halophenyl (e.g., fluorophenyl, chlorophenyl, bromophenyl, iodophenyl), dihalophenyl (e.g., difluorophenyl, dichlorophenyl, dibromophenyl, diiodophenyl), trihalophenyl (e.g., trifluorophenyl, trichlorophenyl, tribromophenyl, triiodophenyl), (trifluoromethyl)phenyl, fluoro(trifluoromethyl)phenyl, chloro(trifluoromethyl)phenyl, bromo(trifluoromethyl)phenyl, iodo(trifluoromethyl)phenyl, tolyl, xylyl, fluorotolyl, chlorotolyl
  • R 5 is selected from OR 10 , C 1 to C 12 alkyl, -L 7 -C 3 -C 6 cycloalkyl, -L 8 -C 2 -C 6 heterocycloalkyl, benzyl, -L 9 -aryl, and -L 10 -heteroaryl, and is optionally substituted with one, two, three, or more substituent groups that are the same or different. Suitable substituent groups include, but are not limited to, F, Cl, Br, I, CF 3 , CH 3 , OCF 3 , OCH 3 , and - CN.
  • Additional R 5 groups include, but are not limited to, optionally substituted phenyl, halophenyl (e.g., fluorophenyl, chlorophenyl, bromophenyl, iodophenyl), dihalophenyl (e.g., difluorophenyl, dichlorophenyl, dibromophenyl, diiodophenyl), trihalophenyl (e.g., trifluorophenyl, trichlorophenyl, tribromophenyl, triiodophenyl), (trifluoromethyl)phenyl, fluoro(trifluoromethyl)phenyl, chloro(trifluoromethyl)phenyl, bromo(trifluoromethyl)phenyl, iodo(trifluoromethyl)phenyl, tolyl, xylyl, fluorotolyl, chlorotolyl, bromotolyl, iodoto
  • R 6 , R 7 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 17 are independently selected from H and C 1 to C 12 alkyl, including C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, C 6 alkyl, C 7 alkyl, C 8 alkyl, C 9 alkyl, C 10 alkyl, C 11 alkyl, and C 12 alkyl.
  • L 1 , L 2 , L 3 , L 4 , L 5 , L 6 , L 7 , L 8 , L 9 , L 10 , L 11 , L 12 , L 13 , L 14 and L 15 are independently selected from null (a bond), C 1 to C 12 alkylene, including C 1 alkylene, C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene, C 6 alkylene, C 7 alkylene, C 8 alkylene, C 9 alkylene, C 10 alkylene, C 11 alkylene, and C 12 alkylene, and C 1 to C 12 alkenylene, including C 1 alkenylene, C 2 alkenylene, C 3 alkenylene, C 4 alkenylene, C 5 alkenylene, C 6 alkenylene, C 7 alkenylene, C 8 alkenylene, C 9 alkenylene, C 10 alkenylene, C 11 alkenylene, and C 12 alkenylene.
  • Exemplary compounds disclosed herein have a formula selected from C256, C259, C265, C267, C276, C277, C288, C309, C311, C280, C300, C313, C314, C320, C323, C326, C328, C334, C342, C240, C241, C246, C248, C251, C255, C260, C261, C262, C263, C264, C266, C268, C278, C281, C282, C287, C289, C295, C296, C297, C301, C304, C305, C307, C310, C322, C336, C339, C340, C341, C362, C279, C285, C286, C299, C306, C330, C344, C345, C346, C347, C348, C356, C357, C358, C359, C360, C361, C363, C364, C284, and salts, esters, or prodrugs thereof.
  • compounds disclosed herein include those of formula VIII as defined above with the proviso that at most two of X 1 , X 2 , X 3 , X 4 , and X 5 are OH.
  • compounds disclosed herein include those of formula VIII as defined above excluding compounds having a formula
  • compounds disclosed herein include those of formula VIII as defined above with the proviso that at most three of X 1 , X 2 , X 3 , X 4 , and X 5 are H.
  • compounds disclosed herein include those of formula VIII or IX as defined above wherein R a is selected from the group consisting of:
  • Exemplary compounds disclosed herein have a formula selected from C152, C155, C173, C189, C191, C197, C224, C292, C293, C294, C153, C162, C163, C165, C188, C195, C157, C158, C182, C183, and salts, esters, or prodrugs thereof. These compounds are depicted in Table 3 herein below. Table 3. Synthesized PAI-1 Inhibitor Compounds No.
  • PAI-1/ uPA IC 50 ( ⁇ M) PAI-1/ tPA IC 50 ( ⁇ M)
  • a TIII/ ⁇ IIa IC 50 ( ⁇ M) C152 1.57 1.71 87 C155 30.44 34.84 2326 19.2 C189 2.29 C191 1.28 C197 0.173 C224 4.34 C292 4.94, 68* C293 77.6, 123* C294 120.5, 234* C153 0.70 1.02 C162 3.90 7.59 C163 0.288 0.611 C165 0.35 0.51 C188 0.12 C195 0.92 C157 0.25 0.98 44.37 C158 2.60 1.44 547 C182 0.033 C183 0.18 * pH 7.4 was used.
  • compounds disclosed herein include those of formula X as defined above wherein R a is selected from the group consisting of butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
  • compounds disclosed herein include those of formula X as defined above wherein R b is selected from the group consisting of butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, fluorophenyl, chlorophenyl, bromophenyl, iodophenyl, trifluoromethylphenyl, and dichlorohydroxyphenyl.
  • Exemplary compounds disclosed herein have a formula selected from C170, C171, C172, C175, C177, C179, C180, C186, C193, C205, C160, C187, C190, C198, C232, C233, C249, C270, C271, C272, C273, C274, C275, C303, C210, and salts, esters, or prodrugs thereof. These compounds are depicted in Table 5 herein below. Table 5. Synthesized PAI-1 Inhibitor Compounds No.
  • PAI-1/uPA IC50 ( ⁇ M) PAI-1/tPA IC 50 ( ⁇ M) A TIII/ ⁇ IIa IC 50 ( ⁇ M) C170 5.49 C171 1.67 C172 1.98 C175 6.74 C177 5.11 C179 2.40 C180 1.34 C186 6.98 C193 552 C205 5.05 C160 39.04 58.16 2326 C187 0.91 C190 9.70 C198 0.051 C232 13.3 C233 74.8 C249 663 C270 29.5 C271 1.82 C272 16.4 C273 55.6 C274 73.6 C275 30.5 C303 12.6*, 13.6 C210 189.6 * pH 7.4 was used.
  • a comparative compound that does not demonstrate PAI-1 inhibitory activity in buffer (40 mM HEPES, 100 mM NaCl, 0.05% Tween-20, 10% DMSO, pH 7.4) in the assay described in Example 11 herein is depicted below.
  • Exemplary compounds disclosed herein have a formula selected from C168, C176, C184, C185, C196, C156, C161, C200, C204, C236, and salts, esters, or prodrugs thereof. These compounds are depicted in Table 7 herein below. Table 7.
  • Synthesized PAI-1 Inhibitor Compounds No. Structure PAI-1/ uPA IC 50 ( ⁇ M) PAI-1/ tPA IC 50 ( ⁇ M) A TIII/ ⁇ IIa IC 50 ( ⁇ M) C168 1.98 C176 0.62 C184 0.59 C185 0.42 C196 0.45 C156 188.7 581.2 C161 3.70 2.21 1670 C200 58.37 C204 0.035 C236 174
  • compounds disclosed herein include those of formula XIII as defined above wherein R a and R b are independently selected from the group consisting of butyl, pentyl, cyclopropyl, phenyl, difluorophenyl, and hydroxyphenyl.
  • Exemplary compounds disclosed herein have a formula selected from C201, C208, C213, C216, C220, C221, C222, C223, and salts, esters, or prodrugs thereof. These compounds are depicted in Table 9 herein below. Table 9. Synthesized PAI-1 Inhibitor Compounds No. Structure PAI-1/ uPA IC 50 in buffer ( ⁇ M) C201 181 C208 77.2 C213 C216 C220 116.46 C221 1608 C222 236 C223 124.6
  • Compounds disclosed herein include those of formula XIV or a salt, ester, or prodrug thereof: wherein R is selected from the group consisting of phenyl and substituted biphenyl.
  • Exemplary compounds disclosed herein have a formula selected from C199, C203, C206, C207, and salts, esters, or prodrugs thereof. These compounds are depicted in Table 11 herein below. Table 11. Synthesized PAI-1 Inhibitor Compounds No. Structure PAI-1/ uPA IC 50 in buffer ( ⁇ M) C199 5.36 C203 17.07 C206 4.96 C207 16.83
  • Compounds disclosed herein include those of formula XVI or a salt, ester, or prodrug thereof: wherein V, n, p, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , Y 1 , Y 2 , R a , R b , Z 1 , Z 2 , Z 3 , and Z 4 are as defined above for formula XV.
  • Compounds disclosed herein include those of formula XVIII or a salt, ester, or prodrug thereof: wherein X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , R b , and Z 4 are as defined above for formula XVII.
  • compounds disclosed herein include those of formula XVII or XVIII as defined above wherein X 1 and X 2 are independently selected from -OH and - OR.
  • Exemplary compounds disclosed herein have a formula selected from C225, C227, C228, C229, and salts, esters, or prodrugs thereof. These compounds are depicted in Table 12 herein below. Table 12. Synthesized PAI-1 Inhibitor Compounds No. Structure PAI-1/ uPA IC 50 in buffer ( ⁇ M) C225 163 C227 205 C228 14.8 C229 1288
  • Compounds for use in the methods disclosed herein include those of formula XX to XXIX or a salt, ester, or prodrug thereof. Compounds of formula XX to XXIX that demonstrate PAI-1 inhibitory activity are depicted in Table 14. Table 14. PAI-1 Inhibitor Compounds Compound No. Structure Supplier XX Chembridge XXI Synthon Labs XXII Vitas M Labs XXIII Chembridge XIV Chembridge XXV Chembridge XXVI Chembridge XXVII Synthon Labs XXVIII Synthon Labs XXIX Enamine
  • the compounds of the present invention can be readily prepared according to the following reaction schemes or modification thereof using readily available starting materials, reagents and conventional synthetic procedures. It is also possible to make use of variants of these process steps, which in themselves are known to and well within the preparatory skill of the medicinal chemist.
  • Derivatives of PAI-1 inhibitors are also included herein. Such derivatives include molecules modified by one or more water soluble polymer molecules, such as polyethylene glycol, or by the addition of polyamino acids, including fusion proteins (procedures for which are well-known in the art). Such derivatization may occur singularly or there may be multiple sites of derivatization.
  • High-throughput screening was carried out using the protocol described below. All screening was performed in the Center for Chemical Genomics in the Life Sciences Institute at the University of Michigan. For assay validation, the Microsource Spectrum 2000 was screened both in HEPES-buffered saline (HBS) and in HBS containing 15 mg/mL BSA. All other libraries were screened in HBS with 15 mg/mL BSA only.
  • HBS HEPES-buffered saline
  • a 2:1 PAI-1:uPA ratio was chosen to enrich for the most active compounds, as greater than half of the PAI-1 must be inactivated before a signal is generated.
  • 3 ⁇ L of the pNA/AMC substrate mixture was added in HBS to yield final concentrations of 200 ⁇ M and 100 ⁇ M, respectively.
  • the mixture of uPA and substrates in the absence of PAI-1 served as a positive control, while the negative control consisted of the mixture uPA and substrates along with PAI-1.
  • the use of the compounds in the treatment of diseases and disorders include treating a disease or disorder associated with elevated levels of PAI-1 comprising administering a PAI-1 inhibitor.
  • the subject is a mammal.
  • the mammalian subject is human.
  • the invention includes PAI-1 inhibitor compounds and their use in the treatment of many diseases or disorders associated with PAI-1 activity.
  • diseases or disorders include, but are not limited to, dysregulation of lipid metabolism, obesity, diabetes, polycystic ovary syndrome, bone loss induced by estrogen deficiency, fibrosis and fibrotic disease, inflammation, cell migration and migration-driven proliferation of cells, and angiogenesis or thrombosis.
  • inhibitors are also contemplated to be useful for modulation of endogenous fibrinolysis, and in conjunction with pharmacologic thrombolysis.
  • the invention includes PAI-1 inhibitor compounds and their use in the treatment of acute diseases associated with high PAI-1 levels, such as, but not limited to, sepsis, myocardial infarction, and thrombosis, compared to PAI-1 levels in normal subjects known not to suffer from sepsis, myocardial infarction, or thrombosis.
  • the PAI-1 inhibitor compounds of the invention are used for treating diseases and disorders associated with high PAI-1 levels, such as, but not limited to, cancer, atherosclerosis, insulin resistance, type 2 diabetes, and fibrotic diseases compared to PAI-1 levels in normal subjects known not to suffer from these diseases or disorders.
  • the invention includes PAI-1 inhibitor compounds for regulating lipid metabolism, including increasing circulating HDL and/or decreasing circulating VLDL in a subject.
  • a PAI-1 inhibitor is useful in the treatment of any condition, including a disease or disorder, wherein the lowering of PAI-1 levels will provide benefits.
  • the PAI-1 inhibitor is useful alone, or in combination with other compounds, which may act as to promote the reduction of PAI-1 levels.
  • compositions comprising one or more PAI-1 inhibitor.
  • the PAI-1 inhibitor is isolated from a known compound or is chemically synthesized.
  • the PAI-1 inhibitor formulation for therapy in a subject is selected based on the route of administration and in certain aspects includes liposome and micelle formulations as well as classic pharmaceutical preparations.
  • the PAI-1 inhibitor is formulated into an appropriate preparation and administered to one or more sites within the subject in a therapeutically effective amount.
  • the PAI-1 inhibitor-based therapy is effected via continuous or intermittent intravenous administration.
  • the PAI-1 inhibitor-based therapy is effected via continuous or intermittent intramuscular or subcutaneous administration.
  • the PAI inhibitor-based therapy is effected via oral or buccal administration.
  • effective amount the invention refers to an amount of PAI-1 inhibitor compound that is sufficient to support an observable change in the level of one or more biological activities of PAI-1, plasminogen activator, HDL, LDL, or VLDL and/or an observable change in an indication for which the treatment is intended.
  • the change may be reduced level of PAI-1 activity.
  • the change is an increase in plasminogen activator, and/or HDL and/or a reduction in LDL and VLDL.
  • administration of the compositions is systemic or local, and in still other aspects comprises a single site injection of a therapeutically-effective amount of the PAI-1 inhibitor composition.
  • Any route known to those of skill in the art for the administration of a therapeutic composition of the invention is contemplated including, for example, intravenous, intramuscular, subcutaneous, oral, or a catheter for long-term administration.
  • the therapeutic composition is delivered to the patient at multiple sites.
  • the multiple administrations are rendered simultaneously or are administered over a period of several hours.
  • the therapeutic composition is taken on a regular basis via oral administration. In certain cases, it is beneficial to provide a continuous flow of the therapeutic composition. Additional therapy is administered on a period basis, for example, daily, weekly, or monthly.
  • combination therapy is specifically contemplated.
  • the PAI-1 inhibitor composition therapy is used similarly in conjunction with other agents commonly used for the treatment of elevated levels of PAI-1, LDL and VLDL.
  • compositions comprising a PAI-1 inhibitor and at least one other therapeutic agent (second therapeutic agent).
  • second therapeutic agent second therapeutic agent
  • the use include administration or inclusion of at least one additional factor or other drug.
  • drugs include drugs used to manage cardiovascular disease including, but not limited to, cholesterol lowering drugs, such as statins, antiinflammatories, and ACE inhibitors.
  • drugs also include drugs targeting neurological disorders including, but not limited to drugs for targeting stroke, seizures, and Alzheimer's Disease.
  • the additional drugs include, but are not limited to, drugs targeting diabetes. These are all disorders associated with elevated levels of PAI-1 and, therefore, it is contemplated that combination therapy may be used with PAI-1 inhibitors and other known therapies.
  • the combination therapy compositions are provided in a combined amount effective to produce the desired therapeutic outcome in the treatment of increased levels of PAI-1, VLDL, or LDL and/or make a detectable change in an indication as described herein.
  • This process involves administering the PAI-1 inhibitor and the second agent(s) or factor(s) at the same time.
  • Uses thus include administering a single composition or pharmacological formulation that includes both agents, or administering two distinct compositions or formulations, at the same time, wherein one composition includes the PAI-1 inhibitor therapeutic composition and the other includes the second therapeutic agent.
  • the PAI-1 inhibitor treatment precedes or follows the second therapeutic agent treatment by intervals ranging from minutes to weeks.
  • the second therapeutic agent and the PAI-1 inhibitor are administered separately, one generally ensures that a significant period of time did not expire between the times of each delivery, such that the second therapeutic agent and the PAI-1 inhibitor are able to exert an advantageously combined effect.
  • one administers both modalities within about 12-24 hours of each other, or alternately, within about 6-12 hours of each other, or alternately, with a delay time of only about 12 hours.
  • Systemic delivery of PAI-1 inhibitors to patients is a very efficient method for delivering a therapeutically effective amount of the compound to counteract the immediate clinical manifestations of a disease or disorder.
  • local delivery of the PAI-1 inhibitor and/or the second therapeutic agent is appropriate in certain circumstances.
  • the PAI-1 inhibitor is delivered to a patient for an extended period of time. It is further contemplated that the PAI-1 inhibitor is taken throughout a patient's lifetime to lower PAI-1, VLDL and/or LDL levels.
  • the invention also comprehends methods using pharmaceutical compositions comprising effective amounts of PAI-1 inhibitor together with pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or carriers useful in PAI-1 inhibitor therapy.
  • compositions include diluents of various buffer content (e.g., Tris-HCl, acetate, phosphate), pH and ionic strength; additives such as detergents and solubilizing agents (e.g., Tween 80, Polysorbate 80), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., thimersol, benzyl alcohol), and bulking substances (e.g., lactose, mannitol); incorporation of the material into particulate preparations of polymeric compounds, such as polylactic acid, polyglycolic acid, etc., or in association with liposomes or micelles.
  • buffer content e.g., Tris-HCl, acetate, phosphate
  • additives e.g., Tween 80, Polysorbate 80
  • anti-oxidants e.g., ascorbic acid, sodium metabisulfite
  • preservatives e.g.,
  • compositions will influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the PAI-1 inhibitor. See, e.g., Remington's Pharmaceutical Sciences, 18th Ed. (1990) Mack Publishing Co., Easton, PA, pages 1435-1712 .
  • Sterile liquid compositions include solutions, suspensions, emulsions, syrups and elixirs.
  • the compounds of this invention may be dissolved or suspended in the pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both.
  • the liquid carrier is one suitable for parental injection.
  • the compounds are sufficiently soluble they can be dissolved directly in normal saline with or without the use of suitable organic solvents, such as propylene glycol or polyethylene glycol.
  • suitable organic solvents such as propylene glycol or polyethylene glycol.
  • dispersions of the finely divided compounds can be made-up in aqueous starch or sodium carboxymethyl cellulose solution, or in a suitable oil, such as arachis oil.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions, can be utilized by intramuscular, intraperitoneal or subcutaneous injection. In many instances a liquid composition form may be used instead of the preferred solid oral method of administration.
  • unit dosage forms of the compounds for standard administration regimens.
  • the composition can be subdivided readily into smaller doses at the physician's direction.
  • unit dosages may be made up in packeted powders, vials or ampoules and, in one aspect, in capsule or tablet form.
  • the active compound present in these unit dosage forms of the composition may be present in an amount of from about one gram to about fifteen grams or more, for single or multiple daily administration, according to the particular need of the patient.
  • the daily dose of active compound will vary depending upon the route of administration, the size, age and sex of the patient, the severity of the disease state, and the response to the therapy as traced by blood analysis and the patient's recovery rate.
  • the precise dosage to be employed depends upon several factors including the host, whether in veterinary medicine or human medicine, the nature and severity of the condition, e.g., disease or disorder, being treated, the mode of administration and the particular active substance employed.
  • the compounds may be administered by any conventional route, in particular enterally, and, in one aspect, orally in the form of tablets or capsules.
  • Administered compounds can be in the free form or pharmaceutically acceptable salt form as appropriate, for use as a pharmaceutical, particularly for use in the prophylactic or curative treatment of atherosclerosis and sequelae (angina pectoris, myocardial infarction, arrhythmias, heart failure, kidney failure, stroke, peripheral arterial occlusion, and related disease states). These measures will slow the rate of progress of the disease state and assist the body in reversing the process direction in a natural manner.
  • PAI-1 inhibitors or derivatives thereof may be formulated for injection, or oral, nasal, pulmonary, topical, or other types of administration as one skilled in the art will recognize.
  • the formulation may be liquid or may be solid, such as lyophilized, for reconstitution.
  • PAI-1 inhibitor or derivatives thereof are useful in the treatment of any of the acute or chronic diseases or disorders associated with increased levels of PAI-1, LDL, or VLDL.
  • Conditions e.g., diseases or disorders
  • Such conditions may be induced as a course of therapy for other purposes, such as chemotherapy or radiation therapy. It is contemplated that such conditions may result from genetic inheritance or be the side effect of another condition or medication.
  • phrases "pharmaceutically or pharmacologically acceptable” refers to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well-known in the art. Except insofar as any conventional media or agent is incompatible with the vectors or cells of the invention, its use in therapeutic compositions is contemplated. Supplementary active ingredients also can be incorporated into the compositions.
  • the active compositions used in the the invention include classic pharmaceutical preparations. Administration of these compositions according to the invention will be via any common route so long as the target tissue is available via that route.
  • the pharmaceutical compositions may be introduced into the subject by any conventional method, e.g., by intravenous, intradermal, intramusclar, intramammary, intraperitoneal, intrathecal, retrobulbar, intrapulmonary (e.g., term release); by oral, sublingual, nasal, anal, vaginal, or transdermal delivery, or by surgical implantation at a particular site.
  • the treatment may consist of a single dose or a plurality of doses over a period of time.
  • the active compounds may be prepared for administration as solutions of free base or pharmacologically acceptable salts in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
  • Dispersions also can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • a coating such as lecithin
  • surfactants for example, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption (for example, aluminum monostearate and gelatin).
  • Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle that contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutical active substances is well-known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients also can be incorporated into the compositions.
  • a PAI-1 inhibitor may be incorporated with excipients and used in the form of non-ingestible mouthwashes and dentifrices.
  • a mouthwash may be prepared incorporating the active ingredient in the required amount in an appropriate solvent, such as a sodium borate solution (Dobell's Solution).
  • the active ingredient may be incorporated into an antiseptic wash containing sodium borate, glycerin and potassium bicarbonate.
  • the active ingredient may also be dispersed in dentifrices, including: gels, pastes, powders and slurries.
  • the active ingredient may be added in a therapeutically effective amount to a paste dentifrice that may include water, binders, abrasives, flavoring agents, foaming agents, and humectants.
  • compositions used according to the invention may be formulated in a neutral or salt form.
  • Pharmaceutically-acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups also can be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
  • compositions used according to the invention may be formulated in micelles or liposomes.
  • Such formulations include sterically stabilized micelles or liposomes and sterically stabilized mixed micelles or liposomes.
  • Such formulations can facilitate intracellular delivery, since lipid bilayers of liposomes and micelles are known to fuse with the plasma membrane of cells and deliver entrapped contents into the intracellular compartment.
  • solutions Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
  • the formulations are easily administered in a variety of dosage forms such as injectable solutions, drug release capsules and the like.
  • parenteral administration in an aqueous solution for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • an effective amount of a PAI-1 inhibitor, or derivatives thereof will be determined by the age, weight, and condition or severity of disease or disorder of the recipient. See, Remington's Pharmaceutical Sciences, supra, pages 697-773 .
  • a dosage of between about 0.001 ⁇ g/kg body weight/day to about 1000 ⁇ g/kg body weight/day may be used, but more or less, as a skilled practitioner will recognize, may be used. Dosing may be one or more times daily, or less frequently, and may be in conjunction with other compositions as described herein. It should be noted that the invention is not limited to the dosages recited herein.
  • the blood levels of PAI-1 and the patient's symptomatic relief analysis may be used to determine whether a larger dose is indicated.
  • the appropriate dosage levels for treatment will thus vary depending, in part, upon the molecule delivered, the indication for which the PAI-1 inhibitor compound is being used, the route of administration, and the size (body weight, body surface or organ size) and condition (the age and general health) of the patient. Accordingly, the clinician may titer the dosage and may modify the route of administration to obtain the optimal therapeutic effect.
  • a typical dosage may range from about 0.1 ⁇ g/kg to up to about 100 mg/kg or more, depending on the factors mentioned above. In other embodiments, the dosage may range from 0.1 ⁇ g/kg up to about 100 mg/kg; or 1 ⁇ g/kg up to about 100 mg/kg; or 5 ⁇ g/kg up to about 100 mg/kg.
  • Unit dose is defined as a discrete amount of a therapeutic composition dispersed in a suitable carrier. Parenteral administration may be carried out with an initial bolus followed by continuous infusion to maintain therapeutic circulating levels of drug product. Those of ordinary skill in the art will readily optimize effective dosages and administration regimens as determined by good medical practice and the clinical condition of the individual patient.
  • the frequency of dosing will depend on the pharmacokinetic parameters of the agents and the routes of administration.
  • the optimal pharmaceutical formulation will be determined by one of skill in the art depending on the route of administration and the desired dosage. See, for example, Remington's Pharmaceutical Sciences, supra, pages 1435-1712 . Such formulations may influence the physical state, stability, rate of in vivo release and rate of in vivo clearance of the administered agents.
  • a suitable dose may be calculated according to body weight, body surface areas or organ size. Further refinement of the calculations necessary to determine the appropriate treatment dose is routinely made by those of ordinary skill in the art without undue experimentation, especially in light of the dosage information and assays disclosed herein, as well as the pharmacokinetic data observed in animals or human clinical trials.
  • Appropriate dosages may be ascertained through the use of established assays for determining level of myocardial infarct in conjunction with relevant dose-response data.
  • the final dosage regimen will be determined by the attending physician, considering factors that modify the action of drugs, e.g., the drug's specific activity, severity of the damage and the responsiveness of the patient, the age, condition, body weight, sex and diet of the patient, the severity of any infection, time of administration and other clinical factors. As studies are conducted, further information will emerge regarding appropriate dosage levels and duration of treatment.
  • compositions and medical uses of the invention are useful in fields of human medicine and veterinary medicine.
  • the subject to be treated is in one aspect a mammal.
  • the mammal is a human.
  • kits containing components comprising a composition comprising a PAI-1 inhibitor; and optionally, at least one additional factor useful in the treatment of the acute and chronic diseases and disorders discussed herein.
  • the invention includes the use of compounds of the invention for the production of a medicament for the treatment or prevention of any disease or disorder discussed herein.
  • the compounds of the invention are inhibitors of the serine protease inhibitor PAI-1, and are therefore useful in the treatment or prophylaxis of those processes which involve the production and/or action of PAI-1.
  • the compounds of the invention in various aspects, are useful in preventing or reducing thrombosis, promoting thrombolysis, reducing fibrosis regulating lipid metabolism as described herein.
  • the compounds of the invention are useful in treating high cholesterol and diseases or disorders associated with elevated levels of PAI-1.
  • the compounds of the invention are useful in treating elevated levels of VLDL or LDL.
  • the compounds of the invention are useful in elevating HDL.
  • the invention includes the uses of these inhibitors for the treatment of many diseases or disorders associated with PAI-1 activity.
  • diseases or disorders include, but are not limited to, inflammation, cell migration and migration-driven proliferation of cells, and angiogenesis or thrombosis.
  • Such inhibitors are also contemplated to be useful for modulation of endogenous fibrinolysis, and in conjunction with pharmacologic thrombolysis.
  • the compounds of the invention are useful in the treatment or prevention of insulin resistance, obesity, non-insulin dependent diabetes mellitus, cardiovascular disease, thrombotic events associated with coronary artery and cerebrovascular disease.
  • the compounds of the invention are also useful for inhibiting the disease process involving the thrombotic and prothrombotic states which include, but are not limited to, formation of atherosclerotic plaques, venous and arterial thrombosis, myocardial ischemia, atrial fibrillation, deep vein thrombosis, coagulation syndromes, pulmonary thrombosis, cerebral thrombosis, thromboembolic complications of surgery (such as joint replacement), and peripheral arterial occlusion. These compounds are also useful in treating stroke associated with or resulting from atrial fibrillation.
  • the compounds of the invention are also used in the treatment or prophylaxis of high cholesterol and diseases or disorders associated with such a condition.
  • the compounds of the invention may also be used in the treatment of diseases or disorders associated with extracellular matrix accumulation, including, but not limited to, renal fibrosis, chronic obstructive pulmonary disease, polycystic ovary syndrome, restenosis, renovascular disease and organ transplant rejection.
  • diseases or disorders associated with extracellular matrix accumulation including, but not limited to, renal fibrosis, chronic obstructive pulmonary disease, polycystic ovary syndrome, restenosis, renovascular disease and organ transplant rejection.
  • the compounds of the invention may also be used in the treatment of malignancies, and diseases or disorders associated with neoangiogenesis (such as diabetic retinopathy).
  • the compounds in the invention may also be used in conjunction with and following processes or procedures involving maintaining blood vessel patency, including vascular surgery, vascular graft and stent patency, organ, tissue and cell implantation and transplantation.
  • the compounds of the invention may also be used in the treatment of Alzheimer's disease.
  • This method may also be characterized as the inhibition of plasminogen activator by PAI-1 in a mammal, particularly a human, experiencing or subject to Alzheimer's disease.
  • This method may also be characterized as a method of increasing or normalizing levels of plasmin concentration in a mammal, particularly those experiencing or subject to Alzheimer's disease.
  • the compounds of the invention may be used for the treatment of myelofibrosis with myeloid metaplasia by regulating stromal cell hyperplasia and increases in extracellular matrix proteins.
  • the compounds of the invention may also be used in conjunction with protease inhibitor-containing highly active antiretroviral therapy (HAART) for the treatment of diseases or disorders which originate from fibrinolytic impairment and hypercoagulability of HIV-1 infected patients receiving such therapy.
  • HAART highly active antiretroviral therapy
  • the compounds of the invention may be used for the treatment of diabetic nephropathy and renal dialysis associated with nephropathy.
  • the compounds of the invention may be used to treat cancer, septicemia, proliferative diseases, such as psoriasis, improving coagulation homeostasis, cerebrovascular diseases, microvascular disease, hypertension, dementia, atherosclerosis, osteoporosis, arthritis, asthma, heart failure, arrhythmia, angina, and as a hormone replacement agent, treating, preventing or reversing progression of atherosclerosis, Alzheimer's disease, osteoporosis, osteopenia; reducing inflammatory markers, fibrinolytic disorder, reducing C-reactive protein, or preventing or treating low grade vascular inflammation, stroke, dementia, coronary heart disease, primary and secondary prevention of myocardial infarction, stable and unstable angina, primary prevention of coronary events, secondary prevention of cardiovascular events, peripheral vascular disease, peripheral arterial disease, acute vascular syndromes, deep vein thrombosis, pulmonary embolism, reducing the risk of undergoing a myocardial revascularization procedure, microvascular diseases such as nephropathy, neuro
  • the compounds of the invention may be used for the topical applications in wound healing for prevention of scarring.
  • the compounds in the invention can be used in the treatment of inflammatory diseases, septic shock and the vascular damage associated with infections and for the treatment of blood and blood products used in dialysis, blood storage in the fluid phase, especially ex vivo platelet aggregation.
  • the compounds in the present invention may also be used in combination with prothrombolytic, fibrinolytic and anticoagulant agents.
  • the present compounds may also be added to human plasma during the analysis of blood chemistry in hospital settings to determine the fibrinolytic capacity thereof.
  • This invention further comprises the use of the compounds for treating, preventing, ameliorating or inhibiting each of the maladies mentioned herein in a mammal, in one aspect, in a human, their use(s) each comprising administering to a mammal in need of such treatment, prevention, amelioration or inhibition a pharmaceutically or therapeutically effective amount of a compound of this invention, or a pharmaceutically acceptable salt, ester, or prodrug form thereof.
  • the compounds of the invention may also be used to treat cancer including, but not limited to, breast and ovarian cancer, and as imaging agents for the identification of metastatic cancers.
  • a pharmaceutically or therapeutically effective amount of a compound herein refers to an amount of the compound in question which will sufficiently inhibit the serine protease inhibitor PAI-1 in the mammal in need thereof to a sufficient extent to provide a desirable improvement in the condition in question or provide sufficient inhibition of the serine protease inhibitor PAI-1 to prevent, inhibit or limit the onset of the physiological basis for the malady or condition in question.
  • PAI-1 PAI-1 inhibitors
  • development of therapeutic agents that act as selective inhibitors of PAI-1 may provide an approach to treat these diseases and disorders.
  • the design and synthesis of a variety of compounds and their structure:activity relationship with PAI-1 is described. Additional synthetic methods for obtaining PAI-1 inhibitors are disclosed in US 2010/0137194 .
  • N -(4-chloro-3-(trifluoromethyl)benzyl)-3-(3,4-dihydroxyphenyl)propanamide (compound C330) was synthesized according to General Procedure A. To a 0 °C solution of 3,4-dihydroxyhydro cinnamic acid (205.8 mg, 1.13 mmol), 4-chloro-3-(trifluoromethyl) benzylamine (0.2 mL, 1.36 mmol), N -methylmorpholine (0.12 mL, 1.13 mmol) and HOBT•H 2 O (173.0 mg, 1.13 mmol) in 5 mL of dry CH 2 Cl 2 and 2 mL of DMF, EDC•HCl (216.6 mg, 1.13 mmol) was added in portions.
  • Step 1 To a 0 °C solution of triphosgene (1 equiv.) in dichloromethane, an appropriately-substituted amine (2.5 equiv.) was added dropwise with stirring. A solution of triethylamine (4.7 equiv.) in dichloromethane was then added. The mixture was allowed to stir for 5 min at 0 °C, then overnight at 25 °C. The reaction mixture was concentrated in vacuo, triturated with ethyl acetate, and filtered. The filtrate was concentrated in vacuo to provide the isocyanate product.
  • Step 2 An ethanolic solution of hydroxylamine (1 equiv.) was added to a -60 °C solution of an appropriately-substituted isocyanate (1 equiv.) in dry dichloromethane. The mixture was allowed to warm to room temperature and stir for 18 hr. The reaction solution was chilled in an ice bath and filtered cold. The filtrate was concentrated in vacuo and the resulting residue was taken up in ethyl acetate and washed with brine (1x). The organic layer was separated, dried, filtered, and concentrated in vacuo. The resulting residue was triturated with chloroform and filtered to provide compounds of formula IV.
  • An ethanolic hydroxylamine solution was prepared by addition at 0 °C of a solution of 25 mmol NaOH in 55 mL absolute ethanol to a stirring suspension of 25 mmol hydroxylamine hydrochloride in 60 mL of absolute ethanol. 8.9 mL of the ethanolic solution of hydroxylamine (1.93 mmol) was added to a -60 °C solution of 4-chloro-3-trifluoromethylbenzyl isocyanate (0.455 g, 1.93 mmol) in 10 mL dry dichloromethane. The mixture was allowed to warm to room temperature and stir for 18 hr. The reaction solution was chilled in an ice bath and filtered cold.
  • Ethyl 2-((4-chloro-3-(trifluoromethyl)benzyl)amino)-2-oxoacetate (compound C256) was synthesized according to General Procedure C. To a 0 °C solution of 4-chloro-3-trifluoromethylbenzylamine (187 ⁇ L, 1.23 mmol) and pyridine (370 ⁇ L, 4.6 mmol) in dichloromethane (6 ml), ethyl 2-chloro-2-oxoacetate (170 ⁇ L, 1.25 mmol) was added dropwise. The solution was removed from the ice bath and left to react for 30 minutes.
  • reaction mixture was washed with 0.2 N HCl (2x), saturated NaHCO 3 (2x), and brine (2x), and was then dried with MgSO 4 , filtered and concentrated in vacuo to afford 0.381 g of compound C256 as a white solid (74%).
  • Carboxylic acids were synthesized according to the procedure described below and as shown in the following scheme:
  • N -(4-chloro-3-(trifluoromethyl)benzyl)- N' -methoxyoxalamide (compound C320) was synthesized according to General Procedure E. To a mixture of 2-((4-chloro-3-(trifluoromethyl)benzyl)amino)-2-oxoacetic acid (103.8 mg, 0.369 mmol), methoxyamine hydrochloride (36.9 mg, 0.426 mmol), 1-hydroxybenzotriazole [HOBt•H 2 O] (65.8 mg, 0.426 mmol), N -methylmorpholine [NMM] (47.0 ⁇ l, 0.426 mmol) in methylene chloride (4 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC•HCl) (82.4 mg, 0.426 mmol) was added and stirred for overnight.
  • EDC•HCl 1-ethyl-3-(3
  • Compound C228 was prepared according to above procedure except that 3,4-dihydroxythiobenazmide was used in place of 3,4-dimethoxythiobenazmide.
  • a fluorometric plate assay was carried out to measure the half maximal inhibitory concentration (IC 50 ) of these compounds on recombinant active human PAI-1 in vitro.
  • IC 50 is a measure of the effectiveness of a compound in inhibiting biological or biochemical function. Stated another way, IC 50 represents the concentration of a drug that is required for 50% inhibition in vitro.
  • the IC 50 of various compounds was measured using a fluorometric plate assay as set out below, and the results are shown in Tables 1 and 12.
  • PAI-1 inhibitor compounds were dissolved in DMSO to a final concentration of (10-50mM), depending upon solubility. Compounds were then diluted in physiologic buffer (40mM HEPES, 100mM NaCl, 0.05% Tween-20, pH7.4) containing 10% DMSO and a dilution series (from 0 to 1000uM depending on solubility) was prepared. 80 ⁇ L of compound was added per well to a 96-well black, opaque microplate in duplicate.
  • physiologic buffer 40mM HEPES, 100mM NaCl, 0.05% Tween-20, pH7.4
  • a dilution series from 0 to 1000uM depending on solubility
  • Tripeptide aminomethylcoumarin Gly-Gly-Arg-AMC (Calbiochem) fluorogenic substrate 100 ⁇ L of 100 ⁇ M was then added and residual uPA activity was determined based upon cleavage of this substrate.
  • the rate of AMC release by uPA (fluorescence) was measured at an excitation wavelength of 370 nm and an emission wavelength of 440 nm.
  • Controls included PAI-1 and uPA in the absence of compound and uPA alone.
  • Percent PAI-1 inhibition was calculated using the following formula: [(uPA alone - uPA/PAI-1 + compound)/(uPA alone - PAI-1/uPA)] ⁇ 100%.
  • the IC 50 was calculated using Graphit (IC 50 0-100%).
  • PAI-1 inhibitor compounds were dissolved in DMSO to a final concentration of (10-50mM), depending upon solubility. Compounds were then diluted in physiologic buffer (40mM HEPES, 100mM NaCl, 0.05% Tween-20, pH7.8) containing (10% DMSO and a dilution series (from 0 to 1000uM depending on solubility) was prepared. 80 ⁇ L of compound was added per well to a 96-well black, opaque microplate in duplicate. 10 ⁇ L of 20 nM PAI-1 in physiologic buffer (pH 7.8) was added and the mixture was agitated for 15 minutes at room temperature.
  • physiologic buffer 40mM HEPES, 100mM NaCl, 0.05% Tween-20, pH7.8
  • a dilution series from 0 to 1000uM depending on solubility
  • Percent PAI-1 inhibition was calculated using the following formula: [(uPA alone - uPA/PAI-1 + compound)/(uPA alone - PAI-1/uPA)] ⁇ 100%.
  • the IC 50 was calculated using Graphit (IC 50 0-100%).
  • PAI-1 inhibitor compounds were dissolved in DMSO to a final concentration of (10-50mM), depending upon solubility. Compounds were then diluted in physiologic buffer (40mM HEPES, 100mM NaCl, 0.05% Tween-20, pH7.8) containing (10% DMSO and a dilution series (from 0 to 1000 ⁇ M depending on solubility) was prepared. 80 ⁇ L of compound was added per well to a 96-well black, opaque microplate in duplicate. 10 ⁇ L of 20 nM recombinant active human PAI-1 (Molecular Innovations) in physiologic buffer, as set out above, was added per well and the mixture was agitated for 15 minutes at room temperature.
  • physiologic buffer 40mM HEPES, 100mM NaCl, 0.05% Tween-20, pH7.8
  • a dilution series from 0 to 1000 ⁇ M depending on solubility
  • Percent PAI-1 inhibition was calculated using the following formula: [(tPA alone - tPA/PAI-1 + compound)/(tPA alone - PAI-1/tPA)] ⁇ 100%.
  • the IC50 is calculated using Graphit (IC50 0-100%).
  • Alpha-thrombin is an active enzyme, related to uPA or tPA. Alpha-thrombin is inhibited by the serpin ATIII, which is closely related to PAI-1. This assay was used therefore as a control in testing for specificity of the PAI-1 inhibitor compounds. Thus, any compound that is specific for inhibiting PAI-1 should not inhibit ATIII.
  • PAI-1 inhibitor compounds were dissolved in DMSO to a final concentration of (10-50mM), depending upon solubility. Compounds were then diluted in physiologic buffer (40mM HEPES, 100 mM NaCl, 0.05% Tween-20, pH7.8) containing (10% DMSO and a dilution series (from 0 to 1000 ⁇ M depending on solubility) was prepared. 80 ⁇ L of compound was added per well to a 96-well black, opaque microplate in duplicate. 10 ⁇ L of 20nM recombinant active anti-thrombin III (ATIII) (Molecular Innovations), a PAI-1-related protein, in physiologic buffer, as set out above, was added and the mixture was agitated for 15 minutes at room temperature.
  • physiologic buffer 40mM HEPES, 100 mM NaCl, 0.05% Tween-20, pH7.8
  • a dilution series from 0 to 1000 ⁇ M depending on solubility
  • Percent PAI-1 inhibition is calculated using the following formula: [( ⁇ IIa alone - ⁇ IIa /PAI-1 + compound)/( ⁇ IIa alone - PAI-1/ ⁇ IIa)] ⁇ 100%.
  • the IC50 is calculated using Graphit (IC50 0-100%).

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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